Of those trauma victims that survive the golden hours immediately following injury, upwards of 50% of these individuals develop some form of multiple organ failure (MODS). This occurs despite the provision of seemingly adequate fluid resuscitation, specific antibiotics, aggressive operative intervention, nutritional support and recently, antibodies to endotoxin as well as various anti-cytokine therapies. In this respect, acute lung injury is reported to be one of the most common forms of organ dysfunction in these individuals. Findings from a number of studies suggest "primed" neutrophils potentially play a key role in mediating this injury. Active suppression of neutrophil apoptotic death is thought to be a central aspect in the progression toward this pathological outcome. This implies that pro-apoptotic therapies might be efficacious. Alternatively, studies of lymphocytes in both septic and traumatized patients/animals indicate an increase in apoptosis in those cell populations and show that experimental anti-apoptotic therapies seem salutary. This raises important concerns about the design of pro- and/or anti-apoptotic therapies being considered for trauma patients. To address this controversy, we will test the hypothesis that the anti-apoptotic mechanisms shown to be beneficial in a clinically relevant model of sepsis, in which acute lung injury appears to be a minor pathological component, may prove to be deleterious in a model where acute lung injury is evident, such as hypotensive shock followed by septic challenge. To test this hypothesis, we have designed four Aims to examine the contribution of the neutrophils' apoptotic process to the development of acute lung injury by using selected knockout/transgenic mice as well as pharmacological interventions directed at genes or mediators thought to be involved in the regulation of A (sub o). The capacity of neutrophils, from mice of differing A (sub o) gene backgrounds and or inhibitor treatments, to produce acute lung injury will also be assessed by both PMN deletional and PMN add-back approaches, as will the role ofmacrophage/ lymphocytes in mediating the development of this state. It is our firm belief that the results of these studies will provide information that will not only allow us to better understand the pathobiology of acute lung injury but also its attenuation.